Direct androgen receptor control of sexually dimorphic gene expression in the mammalian kidney
Direct androgen receptor control of sexually dimorphic gene expression in the mammalian kidney
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DOI：
10.1016/j.devcel.2023.08.010
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发表时间：
2023-11-06
影响因子：
11.8
通讯作者：
McMahon，Andrew P.
中科院分区：
文献类型：
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作者：
Xiong，Lingyun;Liu，Jing;McMahon，Andrew P.
哺乳动物器官在性别之间表现出不同的生理机能、疾病易感性和损伤反应。在小鼠肾脏中，性二态基因活性主要映射到近端小管（PT）节段。批量RNA测序（RNA-seq）数据表明，在性腺控制下，出生后4周和8周建立了性别差异。激素注射研究和雄激素和雌激素受体的遗传去除证明了雄激素受体（AR）介导的PT细胞基因活性调节作为调节机制。有趣的是，热量限制使男性肾脏女性化。单核多组学分析确定了假定的免疫调节区域和协同因子介导小鼠肾脏中PT对AR活性的反应。在人类肾脏中，一组有限的基因显示出保守的性连锁调控，而对小鼠肝脏的分析强调了性二态基因表达调控的器官特异性差异。这些发现提出了有趣的问题的进化，生理意义，疾病和代谢连锁的性二型基因活性。
Mammalian organs exhibit distinct physiology, disease susceptibility, and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA sequencing (RNA-seq) data demonstrated that sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR)-mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putativecis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation, whereas analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, disease, and metabolic linkage of sexually dimorphic gene activity.